1. Field of the Invention
The present invention relates to an antibody which specifically binds to TMAP (tumor associated microtubule associated protein)/CKAP2 (cytoskeleton associated protein 2) or a fragment thereof; and a method for identifying the presence or absence of mitosis and a method for diagnosing cancer prognosis using the same. More specifically, the present invention relates to a composition for diagnosing cancer prognosis comprising an anti-TMAP/CKAP2 antibody or an antigen-binding site thereof, a method for detecting TMAP/CKAP2 using the composition, an anti-TMAP/CKAP2 antibody for diagnosing cancer prognosis, a method for providing information for diagnosing cancer prognosis using the composition, a method for screening a cancer therapeutic agent comprising the step of determining changes in the level of TMAP/CKAP2 antigen-antibody reaction by the treatment of a candidate substance, and a composition for determining cell-division cycles using the composition.
2. Description of the Related Art
In Korea, cancer (malignant neoplasm) is responsible for the death of 62,887 persons per, which corresponds to 25.5% (23.6% for men and 20.5% for women) of the total death toll of 246,515 persons (death rate 512 per hundred thousands of the population) in 2002, ranking it first amongst the causes of death. Lung cancer, gastric cancer, hepatic cancer, colorectal cancer, and pancreatic cancer are in decreasing order the cancers with the highest mortality rates, these five cancers accounting for around 70% of total cancer deaths. Lung cancer, gastric cancer, hepatic cancer and colorectal cancer are the leading causes of cancer death in males, the four cancers account for 28, 147 deaths in that period (around 70% of all cancer deaths (40,177)). For women, 13, 630 deaths, which were around 60% of the total cancer deaths in that period (22,710), were caused by the five cancers of gastric cancer, lung cancer, hepatic cancer, colon cancer and pancreatic cancer.
There are many different types of cancers currently known, reaching several dozen, and cancers are generally classified according to the tissue of origin. Cancer cells grow very rapidly, and invade nearby tissue, leading to metastasis, and thus can directly threaten life. The types of cancer include cerebrospinal tumor, head and neck cancer, lung cancer, breast cancer, thymoma, esophagus cancer, pancreatic cancer, colon cancer, hepatic cancer, biliary tract cancer, etc. Cancer can be also divided further by classification according to pathogenesis or morphology.
Among them, breast cancer is the most common cancer in women other than skin cancer. Even though improved detection methods, mass screening, and advances in treatment over the last decade have significantly improved the outlook for woman diagnosed with breast cancer, many women still-suffer from breast cancer. Approximately 20% of women diagnosed with early-stage breast cancer have a poor ten-year outcome and will suffer disease recurrence, metastasis or death within this time period. On the contrary, the remaining 80% of breast cancer patients diagnosed at an early stage have a good ten-year prognosis. Like this, even though diagnosed with the same stage, patients diagnosed with early-stage breast cancer have different prognosis. Thus, there is an urgent need for evaluation methods capable of distinguishing between them.
Prognostic indicators provide tumor size, nodal status and histological grade, as well as some information regarding prognosis, and suggest response to particular treatments. For example, determination of estrogen (ER) and progesterone (PR) steroid hormone receptor status has become a routine procedure in assessment of breast cancer patients. Tumors that are hormone receptor positive are more likely to respond to hormone therapy and also typically grow less aggressively, thereby resulting in a better prognosis for patients with ER+/PR+ tumors.
Meanwhile, over expression of human epidermal growth factor receptor 2 (HER-2) and a transmembrane tyrosine kinase receptor protein has been correlated with poor breast cancer prognosis (Ross et al. (2003) The Oncologist: 307-325). Currently, Her2/neu expression levels in breast tumors are used to predict response to the anti-Her-2/neu antibody therapeutic agent, trastuzumab (Herceptin; Genentech). In addition, Ki-67 is a non-histone nuclear protein that is expressed during the G1 through M phases of the cell cycle. Studies have shown that Ki-67 overexpression also correlates with poor breast cancer prognosis.
Although current prognostic criteria and molecular markers provide some guidance in predicting patient outcome and selecting appropriate course of treatment, there is still a limit in predicting breast cancer prognosis. Accordingly, there is an urgent need to develop a method for effectively predicting prognosis or to develop an indicator capable of diagnosing them.
With regard to other cancers, lung cancer was a rare disease in the 19th century, but the increased incidence of lung cancer in the 20th century was first attributed to cigarette smoking. In Korea, the incidence of lung cancer is also rapidly increasing. Furthermore, since lung cancer is more fatal than other types of cancer, it remains the leading cause of cancer-related death, even though its incidence does not rank first.
The underlying mechanism of cancer development remains poorly defined, but it is generally understood, that cancer is the result of uncontrolled growth of cells due to genetic mutations that disrupt the normal regulation of cell proliferation. According to stages of cancer development, early cancer stage is defined as tumor invasion confined to the mucosa, which has a considerably better prognosis in most cancers. Thus, it is assumed that early diagnosis and treatment of cancer contribute to the reduction of the mortality rate and cancer treatment cost. However, at an early stage, cancer rarely causes symptoms, if any, such as digestive disorders or abdominal discomfort. Thus, people often ignore these symptoms, leading to an increase in the mortality rate.
To date, cancer diagnosis has been made by physical examination. For example, gastrointestinal X-ray examination methods may be broadly classified into the double contrast method, the compression method, the mucosa relief method, etc, and endoscopic examination is advantageous in that it directly visualizes the internal organ to find small lesions that are not detected by X-ray, and permits biopsy of suspicious lesions, whereby the diagnosis rate is increased. However, endoscopic examination has problems that, there is a chance of contamination, and patients have to experience significant discomfort during the procedure.
In addition, surgical resection of the lesion is the best method that can be conducted for the treatment of cancer, and thus is the only curative treatment currently available for cancer. For complete cure, surgical resection with a maximum surgical margin is generally recommended, but the extent of surgery may be determined in consideration of postoperative complications. However, when cancer spreads to other organs, radical surgery is not possible, and thus other treatments such as chemotherapy are adopted. Anticancer agents currently available serve to temporarily alleviate symptoms or to prevent recurrence and prolong survival time after surgical resection. However, there is a limitation in complete treatment of cancer, and chemotherapy causes severe side effects, and also imposes economic: burden on the patients.
Therefore, it is important to develop a method capable of diagnosing cancer with high sensitivity and specificity, prior to treatment, and the method should be established to diagnose cancer at an early stage. Furthermore, there is a need of personalized diagnostics and therapy based on prediction of cancer prognosis. Until now, there has been no significant progress in a molecular diagnostic technology of determining cancer occurrence by specific detection of a lesion at an early stage, and it is within bounds to say that there is no diagnostic method for particular cancers.
Meanwhile, cell proliferation and growth are essential for cancer development, and most cancer cells undergo abnormal mitotic cell division. A type of cell cycle, normal mitotic cell division is the series of events leading to division of a single cell into two cells, and consists of the G1 phase (preparation step for cell proliferation), S phase (Interphase) (DNA replication), G2 phase (later stage of DNA synthesis) and M phase (Mitotic phase). The major checkpoints that, ensure the fidelity of cell division lie in between the G1 and 3 phase and G2 and M phase, and promote progression of normal cells into the next stage and apoptosis of abnormal cells. In addition, normal cells often leave G1 phase and enter a quiescent G0 phase at the restriction point if there is a shortage of growth factors or nutrients. In particular, M phase is the shortest and the most dramatic phase since at this time the replicated genome is segregated to the opposite pole of the cell and the two daughter cells are generated. The series of events lead to the division of a cell into two daughter cells, and thus this process underlies growth and development in all living organisms. When cells are divided in M phase, they should enter the next phase through the growth in G1 phase. However, cancer cells lose the ability to undergo apoptosis due to DMA damage, and thus cannot progress to the next stage at the checkpoint and stay in M phase. Consequently, excessive rate or cell division leads to a larger number of cells. That is, cancer cells disrupt the normal cell division mechanisms and continuously proliferate in M phase. Therefore, it is expected that a marker capable of detecting abnormal cell cycles can be effectively used, for the development of cancer diagnostic and therapeutic agents.
On the basis of this background, the present inventors have made many efforts to develop a marker capable of detecting cell cycles for the diagnosis of cancer. As a result, they found that detection of TMAP/CKAP2 expression and its level can be used for the examination of specific cell division, cycles and for the diagnosis of cancer, and it can be also used as an index for predicting overall survival and disease-free survival of breast cancer patients, thereby completing the present invention.